Project 3 aims to develop novel curcumin analogs for the treatment of head and neck cancer. Despite advances in targeted therapies in recent years, the long term disease-free and overall survival rates for patients with advanced disease remain poor, and treatment options for recurrent disease are very limited. However, recent advances in our understanding of the molecular basis of head and neck cancer have presented new opportunities for novel therapeutic development. The long-term goal of this application is to develop a new generation of anticancer agents that target critical survival pathways in head and neck cancers. Nature represents a rich source for drug discovery, and our strategy is to start with a safe natural product with a promising activity, such as curcumin. The demonstrated preventive and therapeutic potential of curcumin together with its attractive safety profile begs for immediate efforts to develop curcumin-based agents with improved bioavailability and enhanced anticancer efficacy. In an attempt to retain curcumin's safety profile, while increasing its potency, our preliminary studies have produced a lead compound, EF24. EF24 potently induces apoptosis of various cancer cells, inhibits tumor angiogenesis activity, and decreases tumor size in an animal model. Mechanistic studies have pointed to the NF-kB pathway as a critical molecular target for its potential therapeutic efficacy. To provide alternative candidates, the closely related analog EF31 and their water soluble analogs were synthesized and show promising biological properties. Based on these exciting findings, we propose to rapidly move these curcumin analogs into the clinic. Our study aims to (i) define the mechanism of action of EF24 and its analogs using in vitro and in vivo models, (ii) identify molecular biomarkers that response to the treatment with these drugs, (iii) determine pharmacology and toxicology profiles of these compounds to predict a NOAEL dose in humans, and (iv) select the most promising compounds for clinical evaluation in a phase 0 trial in head and neck cancer patients. Thus, our primary aim is to understand the mechanism of action of novel curcumin analogs, to define their pharmacology and toxicology profiles, and to initiate clinical testing of this new generation of anticancer agents with the ultimate goal of improving treatment options for head and neck cancer patients.